The present invention relates to novel heteroaryl diazabicycloalkanes, which are found to be cholinergic ligands at the nicotinic Acetyl Choline Receptors.
Due to their pharmacological profile the compounds of the invention may be useful for the treatment of diseases or disorders as diverse as those related to the cholinergic system of the central nervous system (CNS), diseases or disorders related to smooth muscle contraction, endocrine diseases or disorders, diseases or disorders related to neurodegeneration, diseases or disorders related to inflammation, pain, and withdrawal symptoms caused by the termination of abuse of chemical substances.
The endogenous cholinergic neurotransmitter, acetylcholine, exert its biological effect via two types of cholinergic receptors, the muscarinic Acetyl Choline Receptors (mAChR) and the nicotinic Acetyl Choline Receptors (nAChR).
As it is well established that muscarinic ACh receptors dominate quantitatively over nicotinic ACh receptors in the brain area important to memory and cognition, and much research aimed at the development of agents for the treatment of memory related disorders have focused on the synthesis of muscarinic ACh receptor modulators.
Recently, however, an interest in the development of nicotinic ACh receptor modulators has emerged. Several diseases are associated with degeneration of the cholinergic system, i.e. senile dementia of the Alzheimer type, vascular dementia and cognitive impairment due to the organic brain damage disease related directly to alcoholism. Indeed several CNS disorders can be attributed to a cholinergic deficiency, a dopaminergic deficiency, an adrenergic deficiency or a serotonergic deficiency.
The present invention is devoted to the provision novel nicotinic receptor modulators, which modulators are useful for the treatment of diseases or disorders related to the cholinergic receptors, and in particular the nicotinic ACh receptor (nAChR).
Due to their pharmacological profile the compounds of the invention may be useful for the treatment of diseases or disorders as diverse as those related to the cholinergic system of the central nervous system (CNS), diseases or disorders related to smooth muscle contraction, endocrine diseases or disorders, diseases or disorders related to neurodegeneration, diseases or disorders related to inflammation, pain, and withdrawal symptoms caused by the termination of abuse of chemical substances.
The compounds of the invention may also be useful as diagnostic tools or monitoring agents in various diagnostic methods, and in particular for in vivo receptor imaging (neuroimaging), and they may be used in labelled or unlabelled form.
In its first aspect the invention provides a diazabicycloalkane derivative of Formula I 
in labelled or unlabelled form, or any of its enantiomers or any mixture of enantiomers, or a pharmaceutically acceptable salt thereof or a prodrug thereof;
wherein
n represents 0, 1 or 2;
Rxe2x80x2 represents hydrogen, an alkyl group, an aryl group, an aralkyl group or a fluorescent group; and
R1 represents a mono- or poly-heterocyclic group,
which heterocyclic group may be substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, methylenedioxy, hydroxy, alkoxy, alkoxy-alkyl, alkoxy-alkoxy, aryloxy, sulfhydryl, thioalkoxy, alkylcarbonyloxy, halogen, CF3, OCF3, CN, and nitro;
or which heterocyclic group may be substituted once with another mono- or poly-heterocyclic group, a mono- or polycyclic aryl group, or a mono- or polycyclic aralkyl group;
and/or which heterocyclic group may be substituted with one or more fluorescent groups.
In another aspect the invention provides a pharmaceutical composition comprising a therapeutically effective amount of the diazabicycloalkane derivative of the invention, or a pharmaceutically acceptable addition salt thereof, together with at least one pharmaceutically acceptable carrier or diluent.
In a third aspect the invention provides an assay kit comprising the pharmaceutical composition of the invention in a unit dosage form in a suitable container.
In a fourth aspect the invention relates to the use of the diazabicycloalkane derivative of the invention for the manufacture of a medicament for the treatment or alleviation of a disease or disorder of a living animal body, including a human, which disease or disorder is responsive to the action of a nicotinic Acetyl Choline Receptor (nAChR) modulator.
In a fifth aspect the invention provides a method of the treatment or alleviation of a disease or disorder of a living animal body, including a human, which disease or disorder is responsive to the action of a nicotinic Acetyl Choline Receptor (nAChR) modulator, which method comprises the step of administering to such a living animal body, including a human, in need thereof a therapeutically effective amount of the diazabicycloalkane derivative of the invention.
In a sixth aspect the invention relates to the use of the diazabicycloalkane derivative of the invention or any of its enantiomers or any mixture of enantiomers, in labelled or unlabelled form, for the manufacture of a diagnostic agent for the diagnosis of a disorder or disease of a living animal body, including a human, which disease or disorder is responsive to the action of a nicotinic Acetyl Choline Receptor (nAChR) modulator.
In a seventh aspect the invention provides a method for the non-invasive determination of the distribution of a tracer compound inside a whole, intact living animal or human body using a physical detection method, wherein the tracer compound is a diazabicycloalkane derivative of the invention, or any of its enantiomers or any mixture of enantiomers, or a pharmaceutically acceptable salt thereof, in labelled or unlabelled form.
Other objects of the invention will be apparent to the person skilled in the art from the following detailed description and examples.